Imidazole propionate and fibrosis in cardiometabolic diseases
IMPACT aims to investigate the role of the microbial metabolite imidazole propionate in promoting fibrosis in heart and liver diseases, potentially leading to new therapeutic strategies.
Projectdetails
Introduction
Fibrosis is a pathological feature caused by excessive extracellular matrix secretion, resulting in scar tissue that causes thickening and loss of tissue mobility, culminating in impaired organ function. It is a common feature of heart failure and non-alcoholic steatohepatitis and an important determinant of morbidity and mortality. However, relatively little is known about the underlying aetiology.
Background
We and others have mapped alterations in the gut microbiota in different cardiometabolic diseases, focusing on the functions performed by the microbiota. IMPACT builds on our work showing that humans with type 2 diabetes have high plasma levels of the microbial metabolite imidazole propionate (ImP) and that ImP impairs insulin signalling through p38gamma.
We also resolved the X-ray crystal structure of urocanate reductase (UrdA), the bacterial enzyme responsible for ImP production. Our recent work showed that ImP is more strongly associated with heart failure and that treatment of mice with ImP promotes both cardiac and liver fibrosis, consistent with studies showing that p38gamma signalling is implicated in fibrosis development.
Objectives
IMPACT will focus on several key objectives:
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Clinical Assessments: Use state-of-the-art clinical assessments to determine how circulating levels of ImP correlate with fibrosis in heart and liver.
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Kinetics of Fibrosis Induction: Explore the kinetics by which ImP induces fibrosis in mice and how this process is associated with immune cell infiltration and disease progression.
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Mechanistic Understanding: Perform similar experiments in mice lacking key target signalling components (e.g., p38gamma), combined with single cell sequencing that will guide us in producing tissue-specific knockouts to elucidate the cellular cross-talk.
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UrdA Inhibitors: Generate UrdA inhibitors and test their potential to reduce ImP production in isolated bacteria, complex microbial communities, and colonised mice.
Conclusion
Thus, IMPACT has the potential of generating new therapies to diseases with unmet clinical needs.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 2.482.678 |
Totale projectbegroting | € 2.482.678 |
Tijdlijn
Startdatum | 1-8-2023 |
Einddatum | 31-7-2028 |
Subsidiejaar | 2023 |
Partners & Locaties
Projectpartners
- GOETEBORGS UNIVERSITETpenvoerder
Land(en)
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Immune-stromal crosstalk in inflammation and fibrosis: Exploiting the spatiotemporal dynamics of the OSM-OSMR axis in inflammatory bowel disease to develop novel antifibrotic therapies
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Inhibitor-Mediated Programming of Glycoforms
The project aims to revolutionize glycan manipulation using Inhibitor-Mediated Programming of Glycoforms (IMProGlyco) to create precision-engineered therapeutic proteins and enhance cellular functions.
Targeting cardiac fibrosis with next generation RNA therapeutics
FIBREX aims to develop an innovative ncRNA-based antisense oligonucleotide therapy targeting Meg3 to reverse cardiac fibrosis and treat heart failure, advancing towards clinical readiness.
Targeting OGG1 in Idiopathic Pulmonary Fibrosis
The TOPFIBRO project aims to advance OXC-201, a novel IPF treatment, through efficacy validation, safety assessments, and regulatory preparations for first-in-human studies, targeting a market launch.